2002 — 2003 |
Tregellas, Jason R |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Fmri of Cholinergic Dysfunction in Schizophrenia @ University of Colorado Denver
[unreadable] DESCRIPTION (provided by applicant): Abnormalities in smooth pursuit eye movements and deficits in auditory sensory gating are two of the best characterized physiological endophenotypes associated with schizophrenia. Transient normalization of both of these sensory deficits by smoking, in addition to evidence from epidemiology, animal models, genetics, molecular biology and post-mortem binding studies, suggests involvement of nicotinic cholinergic receptors in the disease. The functional effect of this putative cholinergic dysfunction on mental processes in individuals with schizophrenia, however, remains unknown. This first aim of this study proposes the use of functional magnetic resonance imaging (fMRl) to characterize the functional neuroanatomy associated with smooth pursuit eye movements in patients with schizophrenia and age-matched healthy controls to determine if failure to properly execute this task in patients with schizophrenia is associated with a detectable, abnormal pattern of neuronal activation. The second aim of his study is to use fMRI to detect differences in functional neuroanatomy between control and patients with schizophrenia are due to nicotinic cholinergic receptor dysfunction by examining task-specific (smooth pursuit eye movement) changes in neuronal activity associated with administration of nicotine to controls and patients with schizophrenia.
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2010 — 2013 |
Cornier, Marc-Andre (co-PI) [⬀] Tregellas, Jason R |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neuronal Responses to Effective Weight Loss Maintenance Strategies @ University of Colorado Denver
DESCRIPTION (provided by applicant): Obesity is a serious and growing public health problem in the United States and the world. While many overweight and obese individuals can lose weight, few can maintain weight loss for substantial periods of time. This suggests that physiological adaptations occur with weight loss that oppose further weight loss and promote weight regain. The weight reduced state is associated with alterations in meal-related hormone responses as well as long-term adiposity signals such as leptin both potentially promoting increased energy intake. While these signals may directly impact energy balance regulation, there is increasing evidence that these physiologic signals interact with reward, behavioral and cognitive systems to ultimately enhance food intake. For example, in normal weight individuals, there appear to be important interactions between environmental food-related cues and brain regions known to be important in the homeostatic regulation of food intake, and these interactions are affected by food intake and energy balance. These responses appear to be altered in obesity and more so following diet-induced weight loss which would favor increase food intake. This inability to properly adapt to the environment may represent an important mechanism for the difficulty of successful long-term weight loss maintenance. Successful weight loss maintenance interventions must, therefore, require control of energy balance via a complex interaction between physiologic and nonphysiologic systems, and understanding these mechanisms will allow for the potential development of new and/or better strategies for weight loss maintenance. Two such successful interventions are weight loss surgery and exercise. While both of these interventions have been shown to been associated with changes or 'normalization' in meal-related hormone responses that might favor reduced food intake, the mechanisms by which these interventions help promote weight loss and prevent weight regain are not well understood. Studies designed to elucidate the mechanisms of successful weight loss maintenance interventions such as these are a critical area for investigation. The overall goal of this proposal is to examine the effects of weight loss surgery and exercise on the neuronal, behavioral and hormonal response to a meal. It is hypothesized that these successful weight loss maintenance interventions will restore the normal neuronal response to a meal and that this improved neuronal response will be associated with changes in both meal associated hormones and appetite ratings. In order to examine these hypotheses we propose to use fMRI to examine the neuronal response to visual food cues before and after a meal as well as to study the hormonal response to a meal in individuals who have undergone Roux-en-Y gastric bypass or gastric banding as compared to diet control and in individuals maintaining weight loss through a supervised exercise intervention as compared to diet control. PUBLIC HEALTH RELEVANCE: Obesity is a serious and growing public health problem in the United States and the world. While many overweight and obese individuals can lose weight, few can maintain weight loss for substantial periods of time. This suggests that adaptations occur with weight loss that oppose further weight loss and promote weight regain. The most successful interventions for sustained weight loss are bariatric surgery and exercise. It is unclear, however, how these interventions help individuals maintain a reduced body weight. By understanding the complex interactions between the brain response to eating and food cues and physiologic changes with these interventions we hope to be able to develop new strategies and/or interventions for sustained weight loss.
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2014 |
Tregellas, Jason R |
S10Activity Code Description: To make available to institutions with a high concentration of NIH extramural research awards, research instruments which will be used on a shared basis. |
3t Mri @ University of Colorado Denver
DESCRIPTION (provided by applicant): This proposal is a request for a 3 Tesla, whole-body, wide-bore magnetic resonance imaging system for the University of Colorado School of Medicine, Anschutz Medical Campus. The proposed instrument (3T Siemens MAGNETOM Skyra) would fulfill unmet research needs while providing greater scientific and funding opportunities for investigators across a wide range of departments and institutions. A major research interest at the UC School of Medicine is understanding and developing better treatments for schizophrenia and related mental illnesses. Because many of these studies involve auditory sensory processing, research is limited by the loud noise generated by our current scanner. The requested 3T Siemens scanner is markedly quieter than our current dated GE 3T MRI scanner, substantially improving our research capabilities in this area. In addition to benefiting our adult sensory processing and drug development studies, quieter scanning also would also greatly benefit a large newly- funded effort to understand the development of sensory processing and cognitive abilities in infants. Our current success rate for scanning infants is approximately 50%. The primary hindrance to scanning success is the noise of our current scanner, which often wakes the sleeping infants. In addition to being substantially quieter, parallel imaging and higher acceleration factors on the new scanner would allow for a shorter overall exam time, additionally increasing the likelihood of scan completion in this population. These factors would also result in less geometric distortion and signal dropout in the hippocampus and prefrontal cortex, brain areas thought to be critically important in the development of mental illness. Another major research focus that would benefit from the new system is our effort to understand the physiological and neurobiological basis of eating disorders, obesity and diabetes. A significant limitation for these studies is the narrow bore diameter of our current MR system. This limitation precludes scanning over 30% of obese subjects. This size limitation also is a key factor in spectroscopic studies of the liver, particulrly for those involving the measurement of 31P and 13C, which require a surface coil. In our present system, it is only feasible to study lean subjects, due to space required for the surface coil. A wide-bore system would enable multinuclear studies of the liver to access mitochondrial metabolism and liver glycogen, both important for diabetes and obesity studies. The proposed new system would also substantially improve important aspects of MRI-related research that would benefit all users, including 1) higher signal-to-noise ratios, 2) access to newer imaging techniques (e.g., arterial spin-labeling) not available on our current platform, 3) smaller magnet size, which can increase patient comfort and 4) elimination of our current limitation on the number of slices/volumes that can be acquired.
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2014 — 2015 |
Tregellas, Jason R |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Neuronal and Behavioral Effects of Implicit Priming in Obese Individuals @ University of Colorado Denver
DESCRIPTION (provided by applicant): Obesity is a significant public health concern associated with an increased mortality risk, and risk of coronary heart disease and type 2 diabetes. Weight loss is associated with reduced comorbid conditions and increased quality-of-life. However, weight loss can be difficult, and preventing subsequent weight regain even more challenging. As such, understanding the mechanisms underlying the regulation of energy balance and identifying strategies for successful weight-loss and maintenance are important goals, and are key components of the Strategic Plan for NIH Obesity Research. Food intake is a complex process involving homeostatic signals (e.g., appetite-related hormones) and non-homeostatic signals (e.g., cognitive factors, reinforcing properties of food). One factor that may contribute to susceptibility to obesity is a high responsivity to high-calorie foods in terms of cognitive factors such as emotional associations, reward value or reinforcing properties of food. Many of these processes involve learned associations that are thought to develop via classical conditioning through repeated pairings with external stimuli, which can influence food preferences and intake. As such, improving our understanding of the neuronal mechanisms underlying these processes and attempting to modify them may be a useful strategy to promote weight loss and maintenance. Therefore, the proposed study aims to investigate the effects of altering food perception on neuronal responses and food intake behaviors by using implicit priming, in which positively or negatively valence images (i.e., images with positive or negative emotional significance) are presented immediately prior to food images, but are not consciously perceived. We hypothesize that this will alter perception of food cues by manipulating affective associations with food items, an effect observed in preliminary data. This approach has the potential to reduce the appeal of high-calorie, in favor of low-calorie foods, which could encourage reduced intake of high-calorie foods, promoting weight loss and maintenance. The project goals are to determine the impact of changing food perceptions on both brain responses to food cues and on food intake behaviors in overweight/obese individuals. Food image ratings and neuronal responses to visual food cues will be assessed before and after either (a) an active implicit priming intervention or (b) a control intervention. In the priming condition, image of high- and low-calorie foods will be paired with implicitly presented (below perceptual threshold) images of either negative or positive valence (high-calorie paired with negative; low-calorie paired with positive). Following fMRI, food intake throughout the day will be measured. The use of neuroimaging in this pilot study will provide a more sensitive measure than behavioral measures alone and will help to identify mechanisms through which the intervention changes behavior. If the project aims are achieved, it would not only yield new information about the neurobiology of food intake behavior, but also could represent a potential novel intervention for treatment and prevention of obesity.
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2014 — 2018 |
Tregellas, Jason R |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neuronal Effects of Exercise On Schizophrenia @ University of Colorado Denver
DESCRIPTION (provided by applicant): Obesity is a profound public health issue and an even more alarming problem for patients with schizophrenia, who are obese at rates twice those observed in the general population. The use of certain neuroleptics to treat the symptoms of schizophrenia contributes greatly to weight gain in the illness. Olanzapine and clozapine, for example, can result in substantial weight gain while neuroleptics such as risperidone appear to cause modest weight gain. There is a relatively rich understanding of the molecular mechanisms of these drugs, yet the processes by which they cause metabolic side effects such as obesity are unknown. While imaging studies by our group and others have begun to improve our understanding of the neuronal processes involved in food intake behavior related to obesity in the general population, these mechanisms have not yet been studied in patients with schizophrenia. The overall goals of this proposal are to improve our understanding of the neuronal mechanisms by which neuroleptics contribute to obesity in schizophrenia and to determine whether an intervention such as exercise causes changes in neuronal response that would predict improved regulation of food intake behavior in schizophrenia. These goals will be addressed with two aims. First, we will determine (a) whether neuronal responses to a meal are altered and are related to food intake behaviors in obese compared to lean patients with schizophrenia and (b) whether neuroleptics that cause the most weight gain in patients are associated with greater alterations in neuronal responses related to food intake behavior compared to those associated with less weight gain. Second, this project will determine if a 12-week exercise intervention, as compared to diet, improves function of brain networks associated with food intake behavior in patients with schizophrenia. Understanding the potential mechanisms of dysregulated or altered food intake in patients with schizophrenia and the effect of neuroleptics will have a significant impact on the field and will elucidate possible mechanisms to help develop better, targeted therapeutic interventions for this population. These goals are in line with both the NIMH Strategic Objective to develop better interventions that incorporate the diverse needs of people with mental illnesses, and the Strategic Plan for NIH Obesity Research, which aims to develop more effective approaches to address the tremendous burden of obesity.
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2015 — 2019 |
Tregellas, Jason R |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Nicotinic Agonist Effects On Bmi and Neuronal Response in Overweight/Obese Adults @ University of Colorado Denver
? DESCRIPTION (provided by applicant): Obesity is a profound public health issue, associated with increased mortality and risk for multiple diseases, including cardiovascular disease, diabetes, musculoskeletal disorders, and cancer. Weight loss in obese individuals reduces many of these risk factors, but weight loss and maintenance can be extremely difficult. Clearly, developing new approaches to treat obesity is an important goal, and is a key component of the Strategic Plan for NIH Obesity Research. A possible novel mechanism for treating obesity is activation of the a7 nicotinic cholinergic receptor. Nicotine's association with reduced body weight, and its ability to suppress appetite, increase energy expenditure and alter feeding patterns is well established. Recent evidence suggests that the a7 nicotinic receptor may play a particularly prominent role in these effects. Recent findings by our group separately examining the neuronal mechanisms of food intake behavior in non-mentally ill subjects and the neurobiology of nicotinic cholinergic dysfunction in schizophrenia unexpectedly have converged, showing that some of the same brain intrinsic network components that are overactive in obese individuals are down-modulated by an a7 nicotinic receptor agonist in patients. Given these effects, we recently conducted an initial study of the effect of the a7 nicotinic receptor partial agonist 3-2,4 dimethoxybenzylidene anabaseine (DMXB-A) on weight, appetite and neuronal measures of the response to visual food cues in patients. These measures were an add- on outcome of a study designed to examine drug effects on cognition. Compared to placebo, DMXB-A was associated with significant weight loss and a reduction in hunger and appetite. Neuronally, DMXB-A was associated with alterations in the same brain regions we previously found to be involved in the response to food intake in lean compared to obese-prone individuals. We also found that the DMXB-A-associated change in insula response to food cues was related to weight change. Considering these preliminary results, and emerging evidence from animal studies, activation of a7 nicotinic receptors may be a novel mechanism to alter neuronal processes of food intake behavior and improve weight management in overweight/obese individuals in the general population. The overall goal of this application is to understand the effects of an a7 nicotinic receptor partial agonist on neuronal, physiological, and behavioral mechanisms of obesity in the general population. It is hoped that results of this study will inform our knowledge of nicotinic cholinergic involvement in obesity, potentially leading to novel treatment strategies to address a critical problem that negatively impacts health and quality of life.
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2021 |
Tregellas, Jason R |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Development of Psychopathology, Psychobiology & Behavior @ University of Colorado Denver
Development is critical for understanding psychopathology, particularly for understanding the precursors and early manifestations of illness. This postdoctoral training program, entering its 39th year, focuses on training scientists in areas related to translational developmental neuroscience. The Developmental Psychobiology Research Group (DPRG) is a multi-specialty, multi-departmental, multi-institutional group of collaborative scientists from throughout the Denver metropolitan region. The DPRG has administered this T32 training program since its inception almost 40 years ago and is requesting an additional five years of funding with six trainees per year for its 2-3 year postdoctoral training program. The program recruits physicians (primarily child psychiatrists) who will generally enter the program with five to seven years of postdoctoral experience and individuals with a PhD, who will generally enter the program with zero to four years of postdoctoral training. Mentoring faculty are chosen based on research accomplishment, a history of successful research collaborations, and a history of successful research mentoring; 100% of the faculty are senior faculty (Associate or full Professors). The program includes both core and individualized curricular components. Core curricular components includes an ongoing work-in-progress seminar with both faculty and trainee involvement, a writing seminar, yearly retreats, career development retreats, and a seminar related to the Responsible Conduct of Research. The individualized curricular components include both class work and direct project experience, including dissemination, mentored by a mentorship team. Ongoing empirically-based review of the program demonstrates both a high level of success of this program's graduates as well as the program's curricular flexibility in responding to the results of those reviews. Evaluation of the program is ongoing. Strengths of the program include the quality of the applicants, a collaborative group of outstanding faculty, interaction of trainees from a variety of disciplines, and a strong evaluation process. The scientists trained by this program become leaders in identifying the child and adolescent precursors to mental illness, and in developing novel strategies for treatment and prevention.
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2021 |
Tregellas, Jason R |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neuronal and Behavioral Effects of An Implicit Priming Approach to Improve Eating Behaviors in Obesity @ University of Colorado Denver
PROJECT SUMMARY/ABSTRACT Weight loss is associated with a reduction in obesity-related health risks, but can be difficult, with preventing subsequent weight regain even more challenging. As such, understanding mechanisms underlying energy balance regulation and identifying strategies for successful weight loss and maintenance are important goals, and are key components of the Strategic Plan for NIH Obesity Research. Food intake is a complex process involving homeostatic signals (e.g., appetite-related hormones) and non-homeostatic signals (e.g., reinforcing properties of food). One factor that may contribute to susceptibility to obesity is a high responsivity to high-calorie foods, which promotes increased caloric intake. Food preferences involve learned associations thought to develop via classical conditioning through repeated pairings with external stimuli. Improving our understanding of the neuronal mechanisms underlying these processes and attempting to modify them may be a useful strategy for weight loss and maintenance. Therefore, the proposed study aims to investigate the neuronal and behavioral effects of an intervention designed to alter affective associations with food, using a novel implicit priming (IP) paradigm, in which positively or negatively valenced images are presented immediately prior to food images, but not consciously perceived. We hypothesize that IP will alter neuronal and behavioral responses related to food intake, reducing the appeal of high-calorie foods and promoting weight loss and maintenance. The project goals are to further delineate the neuronal mechanisms underlying the intervention, establish the impact of IP on longer-term food preferences and eating behavior, and determine if it can facilitate weight- loss maintenance in individuals with overweight/obesity. Effects of IP on neuronal responses to visual food cues and measures of eating behaviors (food intake, preferences) will be measured not only acutely, but also following 12 weeks of weekly IP administrations, within the context of weight-loss maintenance. Weight and body composition will be measured before and after the intervention, and, to assess lasting effects, 12 weeks after the intervention has ended. Participants will be randomized to active IP, control IP (with scrambled images as primes), or to an active control, cue exposure therapy (CET). Sex-based differences will also be examined, as studies have observed women to have stronger, more frequent food cravings, greater neuronal response to hedonic food cues, and greater sensitivity to disgust than men. The use of neuroimaging in this study will provide a more sensitive measure than behavioral measures alone and will help to identify mechanisms through which the intervention changes behavior. If the project aims are achieved, it would not only yield new information about the neurobiology of food intake behavior, but also could represent a potential novel intervention for treatment and prevention of obesity.
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